Is ZBED4 p.Pro625Leu (c.1874C>T) pathogenic?

ZBED4 p.Pro625Leu (c.1874C>T) is classified Uncertain significance in ZBED4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-04). AlphaMissense: likely benign (0.0708); Rare (popmax 0.115%, afr).

How common is ZBED4 p.Pro625Leu (c.1874C>T) in the general population?

ZBED4 p.Pro625Leu (c.1874C>T) is rare (popmax 0.115%, afr) (gnomAD).

What do computational predictors say about ZBED4 p.Pro625Leu (c.1874C>T)?

AlphaMissense predicts likely benign (score 0.0708) — an in-silico prediction, not a clinical call.

ZBED4 p.Pro625Leu

c.1874C>T · rs144634675 · VCV3191809

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0708 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.115%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0708	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -6.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 2.5	GERP 1.7, phastCons 0.018
Regional constraint	o/e 1.08	unconstrained · MANE · 922 bp · p 0.12 · regional, not allelic
Overall
CADD	18.17	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.115% African / African-American · 86/74,914 alleles

Filtering AF 0.0951% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0879%

Overall 0.00734% 118/1,607,640 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.115%	871
Admixed American	0.0117%	8,548
Remaining individualsnot grpmax-eligible	0.00965%	10,367
East Asian	0.00672%	14,879
South Asian	0.0022%	45,498
European (non-Finnish)	0.00119%	83,897

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ZBED4
Protein: p.Pro625Leu
Coding: c.1874C>T
MANE Select: NM_024105 · reported on NM_014838
dbSNP: rs144634675
Type: single nucleotide variant
Location: chr22:49885536 (GRCh38)

Full ZBED4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/zbed4-p-pro625leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown